PDQ&reg Treatment Health Professionals

Important: This information is intended mainly for use by doctors
and other health care professionals. If you have questions about this
topic, you can ask your doctor, or call the Cancer Information Service
at 1-800-4-CANCER (1-800-422-6237).

This treatment information summary on childhood soft tissue sarcoma is an
overview of prognosis, diagnosis, classification, and treatment. The National
Cancer Institute created the PDQ database to increase the availability of new
treatment information and its use in treating patients. Information and
references from the most recently published literature are included after
review by pediatric oncology specialists.

Cancer in children and adolescents is rare. A team approach, incorporating the
skills of the primary care physician, surgical specialists, radiation
oncologist, pediatric hematologist/oncologist, rehabilitation specialist,
pediatric nurse specialists, and social worker is imperative to ensure that
patients receive treatment that will ensure optimal survival results. For
advances to be made in treating these patients, therapy is best delivered in
the context of a clinical trial at a major medical center with expertise in
treating children. Only through entry of all eligible children into
appropriate, well-designed clinical trials will progress be made against these
diseases. Guidelines for pediatric cancer centers and their role in the
treatment of pediatric patients with cancer have been outlined by the American
Academy of Pediatrics.[1]

Pediatric soft tissue sarcomas are a group of malignant tumors that originate
from primitive mesenchymal tissue and account for 7% of all childhood
tumors.[2] Rhabdomyosarcomas, tumors of striated muscle, account for more than
one half of all cases of soft tissue sarcomas in children. (See PDQ
Rhabdomyosarcoma information summary) The remaining nonrhabdomyosarcomatous
soft tissue sarcomas account for approximately 3% of all childhood tumors.[3]
This heterogeneous group of tumors includes neoplasms of smooth muscle
(leiomyosarcoma), connective tissue (fibrous and adipose), vascular tissue
(blood and lymphatic vessels), and the peripheral nervous system.[4] These
tumors are histologically classified according to the adult tissue they most
resemble, and synovial sarcomas, fibrosarcomas, and neurofibrosarcomas
predominate in pediatric patients.[5,6]

Nonrhabdomyosarcomatous soft tissue sarcomas are more common in adults
(approximately 5,700 new cases each year)[4] than in children; therefore, much
of the information regarding the treatment and natural history of children with
these lesions has been on the basis of findings from adult studies. However,
pediatric nonrhabdomyosarcomatous soft tissue sarcomas are often associated
with a better outcome. This difference is most pronounced for infants and
young children (<4 years of age) with fibrosarcoma, whose tumors are locally
aggressive but not metastatic; these patients have an excellent prognosis when
treated with surgery only.[3,4,7] Soft tissue sarcomas in older children and
adolescents often behave similarly to those in adult patients.[3,4]

Although they can develop in any part of the body, nonrhabdomyosarcomatous soft
tissue sarcomas arise most commonly in the trunk and extremities.[5,6] These
neoplasms can present initially as an asymptomatic solid mass, or they may be
symptomatic because of local invasion of adjacent anatomical structures.
Systemic symptoms (e.g., fever, weight loss, and night sweats) are rare.
Hypoglycemia and hypophosphatemic rickets have been reported in cases of
hemangiopericytoma, whereas hyperglycemia has been noted in patients with
fibrosarcoma of the lung.[4]

Genetic and environmental factors influence the development of
nonrhabdomyosarcomatous soft tissue sarcomas. Heritable cancer-associated
changes of the p53 tumor suppressor gene can occur in families with Li-Fraumeni
syndrome.[8] Members of these families have an increased risk of developing
soft tissue tumors, bone sarcomas, breast cancer, brain tumors, and acute
leukemia.[3] Approximately 4% of patients with neurofibromatosis type 1
develop malignant peripheral nerve sheath tumors, which usually develop after a
long latency; some patients develop multiple lesions.[4,9] Some
nonrhabdomyosarcomatous soft tissue sarcomas (particularly malignant fibrous
histiocytoma) can develop within a previously irradiated site; others (e.g.,
leiomyosarcoma) have been linked to Epstein-Barr virus infection in patients
with acquired immune deficiency syndrome.[3,4,10]

The treatment of rhabdomyosarcoma is covered in the treatment information
summary on rhabdomyosarcoma. Extraosseous Ewing's, peripheral
neuroepithelioma, and Askin's tumor are discussed in the treatment information
summary on Ewing's sarcoma.
Because the prognosis and biology of these tumors vary greatly depending on the
age of the patient, the specific histology, the primary site, and the extent of
disease, and because the long-term related morbidity must be minimized while
disease-free survival is maximized, the ideal therapy for each patient must be
carefully and individually determined. Studies have shown that tumor size,
tumor invasiveness, histologic grade, and extent of disease at diagnosis
influence outcome in pediatric patients with nonrhabdomyosarcomatous soft
tissue sarcomas, and these prognostic factors should be weighed before
initiating therapy for these patients.[6,11-13]

Pediatric soft tissue sarcomas are classified histologically according to the
soft tissue cell they resemble and include the following.[1]

tumors of fibrous tissue:

fibromatoses (desmoid tumors)

adult and infantile fibrosarcoma

fibrohistiocytic tumors:

malignant fibrous histiocytoma

tumors of adipose tissue:

liposarcoma

tumors of smooth muscle:

leiomyosarcoma

tumors of blood and lymph vessels:

angiosarcoma

hemangiopericytoma

tumors of synovial tissue:

synovial sarcoma

tumors of peripheral nervous system:

malignant schwannoma (malignant peripheral nerve sheath tumor)

tumors of bone and cartilage:

extraskeletal osteosarcoma

extraskeletal myxoid chondrosarcoma

extraskeletal mesenchymal chondrosarcoma

tumors of more than one tissue type:

malignant mesenchymoma

tumors of unknown histogenesis:

alveolar soft part sarcoma

epithelioid sarcoma

clear cell sarcoma

Nonrhabdomyosarcomatous soft tissue tumors are fairly readily distinguished
from rhabdomyosarcoma or Ewing's family of tumors. To distinguish between
various nonrhabdomyosarcomatous lesions, tumor samples should be carefully
evaluated by using immunocytochemical tests and light and electron
microscopy.[1,2] Many nonrhabdomyosarcomatous soft tissue sarcomas are
characterized by chromosomal abnormalities. Some of these chromosomal
translocations lead to fusion of two disparate genes. The resulting fusion
transcript can be readily detected by using polymerase chain reaction-based
techniques, thus facilitating the diagnosis of those neoplasms that have
translocations. Some of the most frequent aberrations seen in
nonrhabdomyosarcomatous soft tissue tumors are listed in Table 1.[3-5]

In the majority of cases, accurate histopathologic classification of soft
tissue sarcomas does not yield optimal information about their clinical
behavior. Therefore, several histologic parameters including degree of
cellularity, cellular pleomorphism, mitotic activity, degree of necrosis, and
invasive growth are evaluated in the process known as "grading." This process
is used to improve the correlation between histologic findings and clinical
outcome.[6] In children, grading of soft tissue sarcomas is compromised by the
good prognosis of certain tumors such as infantile fibrosarcoma. In addition,
testing of a grading system within the pediatric population is difficult due to
the rarity of these neoplasms. In March 1986, the Pediatric Oncology Group
(POG) conducted a prospective study for pediatric soft tissue sarcomas other
than rhabdomyosarcoma and devised the grading system that is shown below.
Analysis of outcome for patients with localized soft tissue sarcomas other than
rhabdomyosarcoma demonstrated that patients with grade 3 tumors fared
significantly worse than did those with grade 1 or grade 2 lesions. This
finding suggests that this system can accurately predict the clinical behavior
of nonrhabdomyosarcomatous soft tissue tumors in children.[2,6]

Grade 1 lesions:

Myxoid and well differentiated liposarcoma

Deep seated dermatofibrosarcoma protuberans

Well differentiated or infantile (patient </=4 years of age) fibrosarcoma

Well differentiated or infantile (patient </=4 years of age)
hemangiopericytoma

Well differentiated malignant peripheral nerve sheath tumor

Extraskeletal myxoid chondrosarcoma

Angiomatoid malignant fibrous histiocytoma

Grade 2 lesions:

Soft tissue sarcomas not included in grades 1 and 3. In grade 2
lesions, less than 15% of the surface area shows necrosis and there are

less than

five mitotic figures per 10 high-power fields (40X objective). As
secondary criteria of grade 2 tumors, nuclear atypia is not marked, and
the tumor is not markedly cellular.

Grade 3 lesions:

Pleomorphic or round cell liposarcoma

Mesenchymal chondrosarcoma

Extraskeletal osteosarcoma

Triton tumor

Alveolar soft part sarcoma

Any other sarcoma not included in grade 1 in which more than 15% of
surface area is necrotic or in which there are more than five mitotic
per 10 high-power fields (40X objective). Marked atypia and
cellularity are less predictive but may assist in placing tumors in
this category.

Clinical staging has an important role in predicting the clinical outcome and
determining the most effective therapy for pediatric soft tissue sarcomas. As
yet, there is no well-accepted staging system that is applicable to all
childhood sarcomas; the system from the American Joint Commission for Cancer
that is used for adults has not been validated in pediatric studies.[1] Two
systems are currently in use for staging pediatric nonrhabdomyosarcomatous soft
tissue tumors. The surgicopathologic staging system used by the Intergroup
Rhabdomyosarcoma Study (see below) is based on the amount of tumor that remains
after initial surgery and on whether the disease has metastasized.[2]

group IV: any localized or regional tumor with distant metastases
present at the time of diagnosis

Recurrent disease

any soft tissue sarcoma that progresses after radiation therapy,
chemotherapy, or initial surgery

The other schema typically used to stage pediatric soft tissue tumors is the
tumor-node-metastases system of the International Union Against Cancer.[3] In
this staging system, T1 lesions are those that are confined to the organ of
origin; T2 lesions invade adjacent organs. These categories can be
subclassified to reflect the maximum tumor diameter (a: </=5 cm; b: >5 cm).
Nodal involvement is indicated by N1 (N0: no nodal involvement), and the
presence of distant metastases at the time of diagnosis is indicated by the M1
(versus M0) designation. Several adult and pediatric series have shown that
patients with large or invasive tumors have a significantly worse prognosis
than do those with small, noninvasive tumors.

These two staging systems have proven to be of prognostic significance in
pediatric and adult nonrhabdomyosarcomatous soft tissue sarcomas.[4-7] In a
review of a large adult series of non-rhabdo sarcomas, superficial extremity
sarcomas have a better prognosis than deep tumors. Thus, in addition to grade
and size, the depth of invasion of the tumor should be considered.[8]

Because of the rarity of pediatric nonrhabdomyosarcomatous soft tissue
sarcomas, all children, adolescents, and young adults with these tumors should
have their treatment planned by a multidisciplinary team composed of pediatric
oncologists, surgeons, and radiotherapists. To better define the natural
history and response to therapy of these tumors, children with these rare
neoplasms should be considered for entry into national or institutional
treatment protocols.

Wide surgical resection of the primary tumor to yield negative margins remains
the mainstay of therapy for pediatric soft tissue sarcomas other than
rhabdomyosarcoma.[1,2] When there is concern about the adequacy of the
surgical margin, radiation therapy is indicated [3] particularly in high grade
tumors with tumor margins less than 1 cm.[4] By using these two treatment
modalities, local control of the primary tumor can be achieved in more than 80%
of patients.[5]

Therapeutic strategies for children and adolescents with soft tissue tumors are
similar to those for adult patients, although there are important differences.
For example, the biology of the pediatric form of the neoplasm may differ
dramatically from that of the adult lesion. In addition, the morbidity of
radiation therapy in young children may be much greater than that observed in
adults, and limb-sparing procedures are more difficult to perform in pediatric
patients. Further, the concern regarding potential long-term side effects of
combined modality therapy (radiation, surgery, and chemotherapy) is greater for
children, whose survival may be much longer than that of adults. Therefore, to
maximize tumor control and minimize long-term morbidity, treatment must be
individualized for children and adolescents with nonrhabdomyosarcomatous soft
tissue tumors. These patients should be enrolled in prospective studies that
accurately assess any potential complications.[1]

A. Fibrosarcomas and hemangiopericytomas in infants and young children,
desmoid tumors, and angiomatoid malignant fibrous histiocytomas typically are
clinically less aggressive, rarely metastasize, and can be treated with surgery
alone.[1]

Treatment options:

Standard:

For nonmetastatic pediatric nonrhabdomyosarcomatous soft tissue sarcomas,
treatment with surgery alone is often curative.[1-5] Postoperatively,
tumor-free margins must be confirmed through pathologic evaluation, and re-
excision must be performed if the margins are positive. For patients with
local recurrence, re-excision of the mass is indicated in an attempt to
avoid radiation therapy. If further resection is not feasible, postoperative
radiation therapy should be used.[6] In children with infantile
fibrosarcoma, preoperative chemotherapy has made possible a more conservative
surgical approach; agents active in this setting include vincristine,
dactinomycin, cyclophosphamide, and ifosfamide.[1] Responses to presurgical
chemotherapy with similar agents have been reported in cases of infantile
hemangiopericytoma.[1]

Desmoid tumors are well-differentiated fibrous lesions that rarely
metastasize but have a significant potential for local invasiveness and
recurrence. A surgical approach to clear margins is the treatment of
choice. When margins are positive, 70% of patients will have a recurrence
of disease. When complete surgical excision is not feasible and the tumor
poses significant potential for mortality or morbidity, preoperative
strategies that include external-beam radiation therapy, postoperative
interstitial iridium-192, nonsteroidal antiinflammatory agents,
antiestrogens, vinblastine, and methotrexate should be considered.
Partially excised or recurrent lesions that do not pose a significant danger
to vital organs may be monitored closely if other treatment alternatives are
not available.[7-10]

Under clinical evaluation:

Vinblastine and methotrexate in recurrent or unresectable desmoid tumors.

B. The following pediatric neoplasms exhibit similar biologic behavior to those
lesions in adults. Treatment for these tumors will be discussed together.

fibrosarcoma in older children and adolescents

malignant peripheral nerve sheath tumor

liposarcoma

synovial sarcoma

hemangiopericytoma in older children and young adults

malignant fibrous histiocytoma

leiomyosarcoma

Treatment options:

Standard:

Every attempt should be made to resect the primary tumor locally with
negative margins. If the original surgery failed to achieve pathologically
negative tissue margins, a second surgery may be indicated.[2] Although
combined surgery and radiation therapy has dramatically improved outcome in
adults and children with soft tissue sarcomas over the past 20 years,[6] the
morbidity of high-dose radiation therapy should be taken into consideration
in infants and young children with these tumors.[11] The use of
brachytherapy and intraoperative electron irradiation is under study.[12,13]
Preoperative radiation therapy has been associated with excellent local
control rates in adults;[14] this approach has not been used extensively in
pediatric patients. The role of adjuvant (postoperative) chemotherapy
remains controversial. The largest prospective pediatric trial failed to
document any benefit of adjuvant chemotherapy with vincristine, dactinomycin,
cyclophosphamide, and doxorubicin in children with grossly resected
tumors.[15] However, a role for chemotherapy has been suggested with
synovial cell sarcomas based on the German prospective study.[16] In
patients with unresectable or metastatic disease treated with vincristine,
dactinomycin, and cyclophosphamide, the overall and disease-free survival
rates were 31% and 10%, respectively.[17]

Under clinical evaluation:

None at present.

C. Alveolar soft part sarcoma is a tumor of uncertain histogenesis that has
some unique biological features. This neoplasm is characterized by an indolent
clinical course, unresponsiveness to chemotherapy, and usually a fatal outcome
in nearly 50% of cases.[18]

Treatment options:

Standard:

The standard approach is complete surgical resection of the primary lesion.
If complete surgical excision is not feasible, radiation therapy should be
administered. The value of adjuvant chemotherapy in completely resected
alveolar soft part sarcomas remains unproven, particularly because patients
with unresected or metastatic tumors failed to respond to chemotherapeutic
agents frequently used to treat soft tissue sarcomas. Patients with
alveolar soft part sarcomas may relapse several years after a prolonged
period of apparent remission.[19]

Under clinical evaluation:

The role of adjuvant chemotherapy in children with this malignancy has not
been tested. Because these tumors are rare, all children with alveolar soft
part sarcoma should be enrolled in prospective clinical trials.

The prognosis for children with metastatic soft tissue sarcomas is poor,[1-6]
and these children should receive combined treatment with chemotherapy,
radiation therapy, and surgical resection of pulmonary metastases. In a
prospective randomized trial, chemotherapy with vincristine, dactinomycin,
doxorubicin, and cyclophosphamide with or without dacarbazine led to tumor
responses in one third of patients with unresectable or metastatic disease.
However, the estimated 4-year survival rate was poor, with less than one third
of children surviving.[7]

Treatment options:

Standard:

Children with isolated pulmonary metastases should undergo exploratory
thoracotomy in an attempt to resect all gross disease. The estimated 5-year
survival rate after thoracotomy for pulmonary metastasectomy has ranged from
10% to 58% in adult studies. Formal segmentectomy, lobectomy, and
mediastinal lymph node dissection are unnecessary.[8]

Under clinical evaluation:

Vincristine, doxorubicin, and ifosfamide with granulocyte colony-stimulating
factor in patients with unresected or metastatic tumors. The Pediatric
Oncology Group is prospectively evaluating the combination of doxorubicin
and ifosfamide in children with unresected or metastatic soft tissue
sarcomas because several adult trials have suggested that ifosfamide-based
regimens may be superior to other chemotherapeutic regimens for soft tissue
sarcomas.

With the possible exception of infants with congenital fibrosarcoma, the
prognosis for patients with recurrent or progressive disease is poor. The
selection of further treatment depends on many factors, including the site of
recurrence, prior therapy, and individual patient considerations. Local
recurrence or isolated pulmonary recurrence should be treated with complete
surgical excision. All patients with recurrent tumors should be offered
enrollment in current drug studies.

Treatment options:

Standard:

Surgical excision is the standard treatment for recurrent pediatric
nonrhabdomyosarcomatous soft tissue sarcomas. If the patient has not yet
received radiation therapy, adjuvant radiation should be considered after
local excision of the recurrent tumor. Limb-sparing procedures with adjuvant
brachytherapy has been evaluated in adults but has not been studied
extensively in children. For some children with extremity sarcomas who have
received previous radiation therapy, amputation may be the only therapeutic
option. No prospective trial has been able to prove that enhanced local
control of pediatric soft tissue sarcomas will ultimately improve survival.
Therefore, treatment should be individualized in light of the site of
recurrence and biologic characteristics (e.g., grade, invasiveness, and
size) of the tumor. All patients should be considered for enrollment in
clinical trials.